tbuckley/cabot-search huggingface dataset:
Clinical outcomes associated with tislelizumab in patients (pts) with advanced hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (SOR) or lenvatinib (LEN) in RATIONALE-208.
Authors: Julien Edeline, Philippe Merle, Weijia Fang, Eric Assenat, Hongming Pan, Lorenza Rimassa, Zhiwei Li, Jean-Frédéric Blanc, Chia-Jui Yen, Paul J. Ross, Sheng Hu, Tao Zhang, Albert Tran, Guoliang Shao, Mohamed Bouattour, Yajin Chen, John Wu, Vincent Li, Sandra Chica-Duque, Zhenggang Ren
Journal: Journal of Clinical Oncology (2022)

4072 Background: Tislelizumab, an anti-PD-1 monoclonal antibody, demonstrated clinical activity and was well tolerated in pts with previously treated advanced HCC in the Phase 2 RATIONALE-208 study (NCT03419897). At the time of this study, SOR and LEN were recommended first-line treatments for pts with advanced HCC and continue to have an important role in the first-line treatment of HCC despite the recent approval of new immuno-oncology-based combinations (atezolizumab and bevacizumab) in some regions. We report the clinical outcomes of pts with advanced HCC who were previously treated with SOR/LEN. Methods: Pts who had received ≥ 1 prior line of systemic therapy for advanced HCC received tislelizumab 200 mg intravenously once every three weeks. Objective response rate (ORR) by independent review committee (IRC) (ORR IRC ), duration of response by IRC (DOR IRC ), progression-free survival by IRC (PFS IRC ), overall survival (OS), and safety were evaluated in pts who had been previously treated with SOR/LEN. Results: As of February 2020, 249 pts were enrolled and 235 pts had received prior treatment with SOR/LEN, of whom 126 and 109 pts had received 1 or ≥ 2 prior lines of systemic therapy, respectively. At study entry, 211 (89.8%) pts had BCLC stage C and 187 (79.6%) pts had extrahepatic spread. Median follow-up duration for pts previously treated with SOR/LEN was 12.5 months and ORR IRC was 13.6% (95% CI: 9.5, 18.7), including 2 complete responses and 30 partial responses. Median DOR IRC was not reached. Median PFS IRC and OS of pts previously treated with SOR/LEN was 2.7 months (95% CI: 1.6, 2.8) and 13.5 months (95% CI: 10.9, 15.8), respectively. Tislelizumab was generally well tolerated in pts previously treated with SOR/LEN (Table), and the most common treatment-emergent adverse events were increased aspartate aminotransferase (n=70; 28.1%) and alanine aminotransferase (n=52; 20.9%). Conclusions: Tislelizumab was investigated beyond the first-line setting, as effective second- and third-line treatment options are limited for pts with advanced HCC and there is an unmet medical need. This analysis indicates that tislelizumab is clinically active and well tolerated in pts with advanced HCC who have received prior systemic treatment with SOR/LEN. Clinical trial information: NCT03419897. [Table: see text]
Whole exome sequencing facilitated diagnosis of patients with multiple mucinous neoplasms of the female genital tract.
Authors: Fang Zhang, Min Shi, Na Zhao, Peng Guo, Jun Hou, Yang Liu
Journal: Journal of Clinical Oncology (2022)

e17513 Background: The differential diagnosis is challenging in clinical practice, especially among gastric-type AD of the cervix with ovarian metastases, multiple primary mucinous neoplasm in cervix and ovary, and synchronous mucinous metaplasia and neoplasia of the female genital tract (SMMN-FGT). Previous studies have revealed that next-generation sequencing might be a feasible tool in identifying the origin of tumor. Herein, whole exome sequencing (WES) was performed to distinguish patients with metastatic disease. Methods: WES analysis was performed on 28 tumors and 7 normal tissues derived from 8 patients. Each patient had one lesion of the cervix uteri. Most of them had lesions at other anatomical sites, including corpus uteri, ovary, oviduct, vermiform appendix and omentum. Mutations signatures and clonal evaluation inferred from single-nucleotide/copy number variants were explored. Results: Previous studies of multiple types of cancer have identified more than 40 single-base substitution (SBS) signatures. SBS3/6 referring to defective DNA mismatch repair and SBS10 reported in both uterus and colorectal AD were significantly enriched in this study. Next, we found no significant distribution of SBS3/6/10 among tumors at different anatomical sites. These findings indicate that primary cervical/ovarian AD with metastases other than multiple primary cancers was the predominant histology in 8 patients. The association of genomic alterations in POLE/ POLD1/HRR pathway with the distribution of SBS signatures was explored. SBS3 had a trend of significant distribution (p = 0.01) in four patients who had germline alterations in HRR pathway. Furthermore, SBS10 was significantly enriched (p = 0.009) in 2 patients with germline POLE/POLD1 alterations. Clonal evolution analyses revealed that 2 patients were identified as having SMMN-FGT, and other 6 patients had dominant clones in different tumors, which suggested a . Notably, besides the dominant clones and subclones, some tumors also exhibited extra independent clones, which might be the mixed histology of primary and metastatic tumor. In addition, we found the difference of overall survival in patients having gastric-type AD of the cervix with ovarian metastases and cervical AD patients with different FIGO stage disease based on SEER database data. Conclusions: Our study demonstrated that WES might be a feasible tool to distinguish patients having primary cervical AD with multiple metastases from those with multiple primary cancers of the female genital tract, which suggests that WES proved valuable in facilitating the diagnostic workup. A prospective, multi-center, large cohort study is needed to investigate the performance of WES in identifying the origin of tumors in patients with multiple tumors of the FGT.
HGG-10. Efficacy of convection-enhanced delivery of GB-13 (IL13.E13K-PE4E) in an orthotopic xenograft model of high-grade glioma is predicated on IL-13Rα2 expression.
Authors: Julian Rechberger, Kendra Porath, Randy Schrecengost, Jann Sarkaria, David Daniels
Journal: Neuro-Oncology (2022)

Abstract High-grade gliomas (HGG) encompass a large proportion of malignant tumors within the central nervous system. Despite advances in our understanding of underlying disease mechanisms, the prognosis remains dismal and efficacious therapies are lacking. As such, there is a dire, unmet, gap in clinical practice for treating this devastating disease. Here, we performed convection-enhanced delivery (CED) of GB-13 (also known as IL13.E13K-PE4E), a tumor-specific immunotoxin, into the mouse brain in an effort to assess safety and efficacy. Fifty-five nude mice were inoculated with cells from 3 distinct patient-derived HGG cell lines (low, medium and high IL-13Rα2 expression). After tumor size reached a pre-determined threshold, mice underwent stereotactic cannula placement into the tumor followed by a single 40-min ramped infusion (rate 0.2-0.8 ul/min) of GB-13 (volume of infusion 20 ul) at concentrations ranging from 5 to 50 ug/ml. Tumor progression was monitored semiweekly and animals were euthanized at the indication of progressive neurologic deficit. All animals tolerated the infusions without exhibiting any neurological changes. GB-13 decreased tumor burden and prolonged survival in a manner strongly associated with IL-13Rα2 expression. While no survival benefit was observed in animals harboring IL-13Rα2-low expressing HGG, IL-13Rα2-medium and -high animals lived significantly longer after GB-13 infusion than vehicle-treated animals (median survival prolongation &amp;gt;25 days). Postmortem examination of the brains revealed no morphological changes beyond the site of the cannula tract. While GB-13 decreased cell proliferation and increased the number of apoptotic cells, neuronal cell density in ipsilateral brain regions was retained and no monocyte infiltrate was evidenced following GB-13 exposure. These findings indicate that a single therapeutic infusion of GB-13 administered by CED is well tolerated and underscore the potential of IL-13Rα2-targeted therapies in a subset of HGG with increased IL-13Rα2 expression.
Nanosomal docetaxel lipid suspension (NDLS) based (neo) adjuvant chemotherapy improves pathological complete response (pCR) in patients with breast cancer.
Authors: Badiginchala Revathi, Palanki Satya Dattatreya, Attili Venkata Satya Suresh, Sharanabasappa Somanath Nirni, Vindhya Vasini Andra
Journal: Journal of Clinical Oncology (2022)

e12591 Background: Nanosomal docetaxel lipid suspension (NDLS) was developed to overcome toxicity issues associated with conventional docetaxel. We evaluated the safety and efficacy of NDLS versus conventional docetaxel-based neo/adjuvant chemotherapy in patients with breast cancer. Methods: Patients with stage IIb-III breast cancer were randomized (1:1) to receive neoadjuvant doxorubicin and cyclophosphamide (AC) followed by conventional docetaxel (arm A) or NDLS (Doceaqualip; arm B) at a dose 75 mg/m 2 IV every 3-weekly for 4 cycles as neo/adjuvant therapy. Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer received treatment as per clinical practice. The study outcomes included pathologic and clinical response rates (pCR, CR), and overall survival (OS). Results: 60 patients were randomized to arm A (n=30) or arm B (n=30). The baseline characteristics were similar in both groups. The pathological and clinical response rates were comparable between the NDLS and conventional docetaxel arms (P&gt;0.05) (Table). The efficacy outcomes were not affected by the receptor (estrogen, progesterone, and HER2) status. The pCR and CR rates were higher in patients who received neoadjuvant AC followed by neoadjuvant NDLS/T versus neoadjuvant AC followed by adjuvant NDLS/T. At a follow-up of 6 months, median OS was not evaluable in both arms as all patients were alive at follow-up post study completion. Grade 3/4 infusion-related reactions, hyperglycemia and neuropathy were noted in 5, 8 and 3 patients, respectively, in the conventional docetaxel arm while it was not reported in any patient in the NDLS arm. Conclusions: NDLS based neo/adjuvant chemotherapy was efficacious in the treatment of breast cancer and showed comparable pCR, CR and OS rates versus conventional docetaxel. NDLS was better tolerated than conventional docetaxel.[Table: see text]
Associations of modern initial antiretroviral drug regimens with all-cause mortality in adults with HIV in Europe and North America: a cohort study
Authors: Adam Trickey, Lei Zhang, M John Gill, Fabrice Bonnet, Greer Burkholder, Antonella Castagna, Matthias Cavassini, Piotr Cichon, Heidi Crane, Pere Domingo, Sophie Grabar, Jodie Guest, Niels Obel, Mina Psichogiou, Marta Rava, Peter Reiss, Christopher T Rentsch, Melchor Riera, Gundolf Schuettfort, Michael J Silverberg, Colette Smith, Melanie Stecher, Timothy R Sterling, Suzanne M Ingle, Caroline A Sabin, Jonathan A C Sterne
Journal: The Lancet HIV (2022)

Over the past decade, antiretroviral therapy (ART) regimens that include integrase strand inhibitors (INSTIs) have become the most commonly used for people with HIV starting ART. Although trials and observational studies have compared virological failure on INSTI-based with other regimens, few data are available on mortality in people with HIV treated with INSTIs in routine care. Therefore, we compared all-cause mortality between different INSTI-based and non-INSTI-based regimens in adults with HIV starting ART from 2013 to 2018.
Data Sharing and Reanalyses Among Randomized Clinical Trials Published in Surgical Journals Before and After Adoption of a Data Availability and Reproducibility Policy
Authors: Damien Bergeat, Nicolas Lombard, Anis Gasmi, Bastien Le Floch, Florian Naudet
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Clinical trial data sharing holds promise for maximizing the value of clinical research. The International Committee of Medical Journal Editors (ICMJE) adopted a policy promoting data sharing in July 2018. <h3>Objective</h3> To evaluate the association of the ICMJE data sharing policy with data availability and reproducibility of main conclusions among leading surgical journals. <h3>Design, Setting, and Participants</h3> This cross-sectional study, conducted in October 2021, examined randomized clinical trials (RCTs) in 10 leading surgical journals before and after the implementation of the ICMJE data sharing policy in July 2018. <h3>Exposure</h3> Implementation of the ICMJE data sharing policy. <h3>Main Outcomes and Measures</h3> To demonstrate a pre-post increase in data availability from 5% to 25% (α = .05; β = 0.1), 65 RCTs published before and 65 RCTs published after the policy was issued were included, and their data were requested. The primary outcome was data availability (ie, the receipt of sufficient data to enable reanalysis of the primary outcome). When data sharing was available, the primary outcomes reported in the journal articles were reanalyzed to explore reproducibility. The reproducibility features of these studies were detailed. <h3>Results</h3> Data were available for 2 of 65 RCTs (3.1%) published before the ICMJE policy and for 2 of 65 RCTs (3.1%) published after the policy was issued (odds ratio, 1.00; 95% CI, 0.07-14.19;<i>P</i> &gt; .99). A data sharing statement was observed in 11 of 65 RCTs (16.9%) published after the policy vs none before the policy (risk ratio, 2.20; 95% CI, 1.81-2.68;<i>P</i>= .001). Data obtained for reanalysis (n = 4) were not from RCTs published with a data sharing statement. Of the 4 RCTs with available data, all of them had primary outcomes that were fully reproduced. However, discrepancies or inaccuracies that were not associated with study conclusions were identified in 3 RCTs. These concerned the number of patients included in 1 RCT, the management of missing values in another RCT, and discrepant timing for the principal outcome declared in the study registration and reported in the third RCT. <h3>Conclusions and Relevance</h3> This cross-sectional study suggests that data sharing practices are rare in surgical journals despite the ICMJE policy and that most RCTs published in these journals lack transparency. The results of these studies may not be reproducible by external researchers.
The initial outcome of deploying a mortality prediction tool at community oncology practices.
Authors: Ping Ye, Brandon Butler, Duc Vo, Bo He, Brian Turnwald, John Russell Hoverman, Puneeth Indurlal, Jody S. Garey, Susan Nga Hoang
Journal: Journal of Clinical Oncology (2022)

1521 Background: Hospice improves the quality of life and care for cancer patients and reduces the likelihood of unwanted death in the hospital. Advance Care Planning (ACP) allows physicians to proactively initiate hospice and end-of-life discussions with identified patients, promoting timely hospice care enrollment. We developed a machine learning (ML) model to predict 90-day mortality risk for patients with metastatic cancer. The tool was designed to enable earlier ACP discussions leading to increased hospice enrollment. This study assesses the ML tool usage on ACP documentation in a community oncology setting. Methods: Twelve practices across the nation were included in the study, all participating in the Oncology Care Model. Five practices implemented the ML tool during 10/26/2020-9/30/2021, with patients scored every two weeks to provide insights on mortality risk. Patients identified as high-risk were evaluated for ACP utilization, obtained from timely EMR data and historical claims. Seven practices did not implement the ML tool and served as the control for the study. Results: A total of 1,663 patients were predicted to have a high risk of mortality at the 12 practices during the timeframe. The median age was 74 years. 53% of patients were males, and 47% were females. ACP documentation varied among the practices. The range was 19.4%-55.8% among ML tool participating practices and 7.4%-31.0% among non-participating practices. The weighted mean of ACP utilization was 34.4% for participating practices and 14.0% for non-participating practices. Compared with non-participating practices, the ACP rate increased significantly by 2.5-fold for participating practices (p-value = 0.03, two-sided T-test). Conclusions: This initial outcome study showed improved ACP documentation after deploying a mortality prediction tool in a community oncology setting. We are currently working on propensity score matching and regression analysis to reduce the effect of confounding factors such as practices, patient demographics, diagnosis, and treatment. Future studies will evaluate the impact of mortality tool use on other outcomes, including hospice enrollment, emergency department visits, and hospital admission. Implementing the mortality prediction tool is an ongoing effort with more practices planned to adopt.
PACSIN3 is a novel biomarker for platinum resistance BRCA mutated platinum resistance epithelial ovarian cancer.
Authors: Gwan Hee Han, Hanbyoul Cho, Hee Yun, Jae-Hoon Kim
Journal: Journal of Clinical Oncology (2022)

e17540 Background: Mutations in breast cancer susceptibility gene type 1 and type 2 (BRCA1 and BRCA2) put women at a higher risk of developing epithelial ovarian cancer (EOC). In individual carrying BRCA1 mutation has about 39-49% of the probability developing EOC in a lifetime. With BRCA2 mutations, the probability of developing EOC is about 11- 18 %. EOC patients with BRCA mutations shows an advanced histological grade compared to patients with BRCA wile type and respond better to platinum therapy, showing better survival. Patients with BRCA mutation shows better response to the platinum therapy, because in the absence of functional BRCA protein, cells fail to repair intra-strand crosslinks formed by DNA cross linking agents such as platinum drugs, leading to apoptotic cell death. However, despite the good response to platinum-based chemotherapy, EOC patients inevitably develop resistance to platinum drugs resulting in disease recurrent and is a major roadblock in a clinical management of cancer that carry BRCA mutation. Therefore, here we investigated the potential novel biomarkers with bioinformatics tools by analyzing an our own RNA sequencing. Methods: RNA sequencing data from 4 platinum sensitive BRCA mutated EOC patients and 4 Platinum resistance BRCA mutated EOC patients were analysed with various bioinformatic tools including Spatial Analysis of Functional Enrichment (SAFE) analysis, and the bioinformatic analysis result was verified with variuos ovarian cancer cell lines and public data. Results: Therefore, here we investigated the potential novel biomarkers with bioinformatics tools by analyzing an our own RNA sequencing data from 4 platinum sensitive BRCA mutated EOC patients and 4 Platinum resistance BRCA mutated EOC patients. The results of our study showed 308 total differentially expressed genes (DEGs) with 138 upregulated genes and 170 downregulated genes. By applying Spatial Analysis of Functional Enrichment (SAFE) analysis, we investigated that G2/M transition of mitotic cell cycle, MAPK cascade, double strand break repair via homologous recombination were the enriched pathways with upregulation of PABPC1, DCAF13, RAD21, PACSIN3 and downregulation of GCG11, HECW2, PSMA1. Their altered expression was verified in ovarian cancer cell lines and public database which showed the significant altered expression of PACSIN3 was observed in ovarian cancer cell lines suggesting as a potential biomarker for EOC treatment. Conclusions: Platinum resistance BRCA mutation EOC is an important issue to overcome the low survival rate for EOC patients. However, until now, there was relatively not much studies in discovring the biomarker or candidate gene of target therapy. Therefore, here we suggest the PACSIN3 as a new candidate gene for target therapy in platinum resistance BRCA mutation EOC.
Induction chemotherapy using carboplatin and paclitaxel followed by hypofractionated radiation therapy in locally advanced hypopharyngeal and laryngeal squamous cell cancer.
Authors: Famya Abdullah, Allah Rakha Adil, Muhammad Saeed Akhtar, Arif Moin Quraishi, Quratul Ain Hashmi, Amir Sattar, Isharat Shehrood Sanwal, Abdul Mateen
Journal: Journal of Clinical Oncology (2022)

e18039 Background: Head and neck cancer (HNC) is one of the most common cancers in Pakistan due to excessive use of chewable tobacco. Locoregional control is not optimum due to advanced stage at presentation and suboptimal cancer treatment facilities. Innovations in treatment schedules are of utmost importance to tackle the problem of overburden of patients and shortage of resources for radiation therapy in the country. The aim of the study is to assess the efficacy of induction chemotherapy with carboplatin and paclitaxel (CP) followed by hypofractionated radiotherapy (HRT) in patients with locally advanced laryngeal and hypopharyngeal cancers. Methods: A total of 68 patients with biopsy proven HNC were included. Patients having primary tumor in larynx (35) and hypopharynx (33) with TNM stage III to IVB were selected. The patients were planned for three cycles of CP every three weeks in a dose of AUC = 5 and 175 mg/m² on day 1 of each cycle respectively. After three cycles of chemotherapy, patients were planned for hypofractionated radiotherapy (HRT). A total of 55 Gray (Gy) was planned with 2.75 Gy per fraction and five fractions a week. Spinal cord dose was limited to 33 Gy. Response Evaluation Criteria in Solid Tumor (RECIST) was used to assess various response rates using computed tomography (CT) six weeks after completion of HRT. Patients were followed for a median of 27.4 months to assess disease free survival (DFS) and overall survival (OS). Results: 61 patients (90%) were available for assessment. Others were excluded due to inability to complete the planned treatment. Eight patients (12%) showed disease progression during treatment and were switched to other form of treatment. Seven patients (10%) showed grade 3 mucosal toxicity and needed treatment interruption. Thirteen patients (19%) showed hematological related grade 1-2 toxicity. The complete response (CR) was seen in 18 (35%), partial response (PR) in 27 (52%) and stable disease SD in 7 (13%) patients. Three year DFS and OS were 45% and 58% respectively. Mean and median DFS (year) were 3.67±0.13 (95% confidence interval [CI] 3.19-3.94) and 4.24±0.43 (CI 3.46-4.52) respectively. Mean and median OS (year) were 3.89±0.11 (CI 3.72-4.15) and 4.12±0.23 (CI 3.87-4.38) respectively. Conclusions: Induction CP followed by HRT is a reasonable in locally advanced laryngeal and hypopharyngeal cancer. A larger phase III randomized trial will be better to define its role before routinely recommending this schedule in these patients.
Efficacy and safety of percutaneous nephrolithotomy in patients with chronic kidney disease: Outcomes from a tertiary care center
Authors: H.S. Talwar, V.K. Panwar, A. Mittal, J. Tosh, G. Singh, R. Ranjan, R.P. Ghorai, S. Kumar, S. Navriya, A.K. Mandal
Journal: European Urology (2022)